SAR of benzoylpyridines and benzophenones as p38alpha MAP kinase inhibitors with oral activity

Laszlo Revesz; Ernst Blum; Franco E Di Padova; Thomas Buhl; Roland Feifel; Hermann Gram; Peter Hiestand; Ute Manning; Gerard Rucklin

doi:10.1016/j.bmcl.2004.03.111

SAR of benzoylpyridines and benzophenones as p38alpha MAP kinase inhibitors with oral activity

Bioorg Med Chem Lett. 2004 Jul 5;14(13):3601-5. doi: 10.1016/j.bmcl.2004.03.111.

Authors

Laszlo Revesz¹, Ernst Blum, Franco E Di Padova, Thomas Buhl, Roland Feifel, Hermann Gram, Peter Hiestand, Ute Manning, Gerard Rucklin

Affiliation

¹ Novartis Institutes for BioMedical Research, Arthritis and Bone Metabolism, CH-4002 Basel, Switzerland. laszlo.revesz@pharma.novartis.com

PMID: 15177483
DOI: 10.1016/j.bmcl.2004.03.111

Abstract

Benzoylpyridines and benzophenones were synthesized and evaluated in vitro as p38alpha inhibitors and in vivo in several models of rheumatoid arthritis. Oral activity was found to depend upon substitution: 1,1-dimethylpropynylamine substituted benzophenone 10b (IC50: 14 nM) and pyridinoyl substituted benzimidazole 17b (IC50: 21 nM) showed highest efficacy and selectivity with ED50s of 9.5 and 8.6 mg/kg p.o. in CIA.

MeSH terms

Animals
Arthritis, Experimental / chemically induced
Arthritis, Experimental / drug therapy
Benzophenones / chemical synthesis*
Benzophenones / pharmacology
Benzophenones / therapeutic use
Disease Models, Animal
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / pharmacology
Enzyme Inhibitors / therapeutic use
Inhibitory Concentration 50
Mouth / metabolism*
Pyridines / chemical synthesis*
Pyridines / pharmacology
Pyridines / therapeutic use
Rats
Structure-Activity Relationship
p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors*

Substances

Benzophenones
Enzyme Inhibitors
Pyridines
benzophenone
p38 Mitogen-Activated Protein Kinases